“Cannabidiol (CBD) found in Cannabis sativa is a non-psychoactive compound which is capable of binding to CB1 and CB2 receptors. CBD has recently gained interest in dentistry although it has not been explored sufficiently yet.
The therapeutic effects of CBD include anti-inflammatory, analgesic, antioxidant, biological and osteoinductive properties. The aim of this review is to highlight these effects with respect to various oral conditions and shed light on the current limitations and prospects for the use of CBD in maintaining oral health.”
“CBD are potent non-psychoactive drug which when used in appropriate proportions under proper guidelines hold the potential to drastically change the current state of dental sciences. However, future researches are imperative focusing on the nature, mechanism, formulations as well as modes of administration to understand this drug thoroughly. Nonetheless, due to its properties such as anti-inflammation, antioxidation, biological nature, analgesia as well as osteoinduction; it is a drug with promising future in dentistry.”
“Background: Depression is a chronic psychiatric disease of multifactorial etiology, and its pathophysiology is not fully understood. Stress and other chronic inflammatory pathologies are shared risk factors for psychiatric diseases, and comorbidities are features of major depression. Epidemiological evidence suggests that periodontitis, as a source of low-grade chronic systemic inflammation, may be associated with depression, but the underlying mechanisms are not well understood.
Methods: Periodontitis (P) was induced in Wistar: Han rats through oral gavage with the pathogenic bacteria Porphyromonas gingivalis and Fusobacterium nucleatum for 12 weeks, followed by 3 weeks of chronic mild stress (CMS) to induce depressive-like behavior. The following four groups were established (n = 12 rats/group): periodontitis and CMS (P + CMS+), periodontitis without CMS, CMS without periodontitis, and control. The morphology and inflammatory phenotype of microglia in the frontal cortex (FC) were studied using immunofluorescence and bioinformatics tools. The endocannabinoid (EC) signaling and proteins related to synaptic plasticity were analyzed in FC samples using biochemical and immunohistochemical techniques.
Results: Ultrastructural and fractal analyses of FC revealed a significant increase in the complexity and heterogeneity of Iba1 + parenchymal microglia in the combined experimental model (P + CMS+) and increased expression of the proinflammatory marker inducible nitric oxide synthase (iNOS), while there were no changes in the expression of cannabinoid receptor 2 (CB2). In the FC protein extracts of the P + CMS + animals, there was a decrease in the levels of the EC metabolic enzymes N-acyl phosphatidylethanolamine-specific phospholipase D (NAPE-PLD), diacylglycerol lipase (DAGL), and monoacylglycerol lipase (MAGL) compared to those in the controls, which extended to protein expression in neurons and in FC extracts of cannabinoid receptor 1 (CB1) and to the intracellular signaling molecules phosphatidylinositol-3-kinase (PI3K), protein kinase B (Akt) and extracellular signal-regulated kinase 1/2 (ERK1/2). The protein levels of brain-derived neurotrophic factor (BDNF) and synaptophysin were also lower in P + CMS + animals than in controls.
Conclusions: The combined effects on microglial morphology and inflammatory phenotype, the EC signaling, and proteins related to synaptic plasticity in P + CMS + animals may represent relevant mechanisms explaining the association between periodontitis and depression. These findings highlight potential therapeutic targets that warrant further investigation.”
“This integrative review addresses the potential of the Endocannabinoid System (ES) and cannabinoids in the pathogenesis and treatment of periodontal disease (PD). Cannabinoid receptors are expressed in healthy and inflamed periodontal tissues, indicating a potential regulatory role for SEC in oral homeostasis.
Healthy periodontal cells express more CB1 receptors, while inflamed sites show increased CB2 receptors. This suggests a dynamic involvement of the SEC in the inflammatory response associated with PD. Cannabinoids such as cannabidiol (CBD) and cannabinoid receptor agonists such as HU-308, anandamide (AEA), and methanamide (Meta-AEA) have demonstrated promising therapeutic potential in studies.
CBD has been associated with the control of bone resorption, antibacterial activity, and increased production of gingival fibroblasts, indicating effects in mitigating the progression of PD. HU-308 demonstrated preventive effects against alveolar bone loss, and anti-inflammatory, osteoprotective, and pro-homeostatic properties in animal models of periodontitis. AEA and Meta-AEA have anti-inflammatory effects by reducing pro-inflammatory mediators such as IL-1, IL-6, and TNF-α.
The activation of cannabinoid receptors attenuates inflammatory processes, inhibits alveolar bone loss, exerts antibacterial effects, and promotes tissue repair. However, clinical trials are especially needed to validate these results and explore the therapeutic potential of cannabinoids in the treatment of PD in humans.”
“Preclinical studies evidence the positive role of the Endocannabinoid System (ECS) and different types of cannabinoids—such as endogenous (anandamide (AEA)), synthetic (methanandamide (Meta-AEA), and HU-308), and natural (Δ9-tetrahydrocannabinol (THC), cannabidiol (CBD))—in the pathogenesis and therapeutics of conditions affecting oral tissues and cells. Notable contributions of this system and its ligands include the potential for preventing bone resorption, anti-inflammatory effects, tissue repair capabilities, and antimicrobial effects”
“Purpose: Periodontitis is an inflammatory disease that results in the loss of periodontal tissue. The endocannabinoid system has anti-inflammatory properties and displays considerable potential for tissue regeneration. In this study, we aimed to explore whether the activation of this system can alleviate or reverse the inflammatory phenotype of human periodontal ligament stem cells (hPDLSCs) induced by exposure to the inflammagen lipopolysaccharide (LPS).
Methods: We investigated the effects of activating specific cannabinoid receptors (CB1 and CB2) on the inflammatory phenotype of LPS-stimulated hPDLSCs. The exogenous ligands WIN55,212-2 and JWH-133 were employed to target the cannabinoid receptors. We conducted a thorough assessment of cell proliferation, metabolic activity, and adipogenic, osteogenic, and chondrogenic differentiation potential. Additionally, we measured cytokine release using enzyme-linked immunosorbent assays.
Results: Exposure to Porphyromonas gingivalis lipopolysaccharide (Pg-LPS) caused an increase in cell proliferation while decreasing metabolic activity. While this exposure did not influence adipogenic or chondrogenic differentiation, it did result in reduced osteogenesis. Additionally, LPS induced the release of interleukin (IL)-6, IL-8, and monocyte chemoattractant protein 1. Immunolabeling revealed the presence of CB1 and CB2 on the cellular membrane, with these receptors playing distinct roles in hPDLSCs. The CB1 agonist WIN55,212-2 was found to increase metabolic activity and promote adipogenic differentiation, whereas the CB2 agonist JWH-133 promoted cell proliferation and osteogenic differentiation. When hPDLSCs were co-exposed to Pg-LPS and CB ligands, JWH-133 slightly ameliorated the inhibition of osteogenic differentiation and suppressed the release of inflammatory cytokines.
Conclusions: This study clarifies the effects of specific CB receptor activation on hPDLCs and the inflammatory phenotype. Stimulation of the endocannabinoid system through the manipulation of endogenous or the application of exogenous cannabinoids in vivo may represent a potent therapeutic option for combating periodontal inflammatory disorders.”
“Design: This study is a randomised, placebo-controlled, triple-arm, phase IIA clinical trial with double masking which investigates the effectiveness and safety of Cannabidiol (CBD) as an analgesic for acute dental pain. The intervention drug, Epidiolex is an FDA-approved CBD oral solution (100 mg/ml) derived from the cannabis plant. The psychoactive ingredient tetrahydrocannabinol (THC) is not included. The maximum recommended daily dose of Epidiolex is 20 mg/kg. 64 patients with moderate-severe odontogenic pain participated in the study and REDCap software was utilised to randomly assign participants into groups: CBD10 (10 mg/kg), CBD20 (20 mg/kg) and placebo. A single dose of the respective oral solution was administered, and participants monitored for 3 h. Patients remained blinded to group assignment, as did the outcome assessor. The provider was not blinded. The primary outcome measure was VAS (visual analogue scale) pain difference, compared to baseline and recorded at 7 subsequent marked times following administration (15, 30, 45, 60, 90, 120, 180 min). Additional outcome measures were also recorded: changes in bite force, pain intensity differences, the onset of significant pain relief, the maximum pain relief, psychoactive effects, mood changes and adverse events.
Case selection: 40 female and 21 male patients with moderate-severe odontogenic pain (defined as ≥30 on a 100 mm VAS) with a diagnosis of irreversible pulpitis or pulp necrosis and symptomatic apical periodontitis were included. Participation required a negative test for recent drug and alcohol use, a negative pregnancy test and no use of analgesics within 6 h of the trial. Pregnancy, breastfeeding, hepatic impairment, recreational cannabis users and patients taking CBD metabolising drugs were excluded along with those with an ASA classification above III. Patient characteristics recorded included: age, gender, race, tooth type affected, weight and BMI.
Data analysis: Mixed model analysis was used to compare numerical variables among the cohorts at the marked time intervals. VAS, bite force, Bowdle and Bond/Lader questionnaires were recorded. Inter-group analysis was completed using parametric and non-parametric post-hoc tests, including Holm-Bonferroni adjustment and the Shapiro-Wilk test, to evaluate data normality. NNTs were calculated for both CBD doses- the number of patients needing treatment before one patient experiences a minimum of 50% pain relief. X² tests were used to analyse categorical variables: pain intensity and adverse events. JMP software was used for the statistical analysis.
Results: 64 participants had originally enroled in the study, but three were excluded from data analysis due to ‘unrealistic results’, reporting complete pain relief within the first 15 min. 20 participants were given CBD10, 20 were given CBD20 and 21 placebo. 68% of the participants were Hispanic/Latino whilst 11% were white. The average age was 44 +/- 13.7. There was equal distribution of age, sex, race, tooth type, weight and body mass index (p > 0.05). No subject required rescue pain relief during the 3-h observation period. Compared to baseline VAS, significant pain relief was seen 30 min after drug administration for CBD10, versus after 15 min for CBD20 (p < 0.05). Pain reduction reached 50% at 60 min for CBD10 and at 120 min for CBD20. Both reported maximum pain reduction of 73% of baseline at 180 min. 33% pain reduction from baseline was seen in the placebo group, with a median VAS pain of 67% at 180 min. 45.4% of CBD10 and 46.6% of CBD20 required pain relief after 1-6 h, versus 37.5% of placebo (p > 0.05). Bite force increase was seen in both CBD10 and CBD20 groups at 90 and 180 min, versus no significant differences between time points in the placebo group. On assessing pain intensity, pain reduction was significantly associated with increasing time in the CBD groups (p < 0.001), versus no significant association with the placebo group (p = 0.0521). No statistically significant differences were seen between and within the groups for Bowdle or Bond/Lader questions (p > 0.05). In the 3 h observation period, CBD10 experienced 14 times more sedation symptoms versus placebo (p < 0.05), whilst CBD20 experienced this 8 times more (p < 0.05). Within the 3 h, CBD20 were 10-fold more likely to have diarrhoea and abdominal pain (p < 0.05), with some experiencing pain beyond the 3 h but resolving within the day.
Conclusions: Based on this randomised clinical trial, pure CBD drug Epidiolex demonstrates effective analgesia against acute toothache.”
“Objective: To evaluate the in vitro antimicrobial and antibiofilm properties and the immune modulatory activity of cannabidiol (CBD) and cannabigerol (CBG) on oral bacteria and periodontal ligament fibroblasts (PLF).
Methods: Cytotoxicity was assessed by propidium iodide flow cytometry on fibroblasts derived from the periodontal ligament. The minimum inhibitory concentration (MIC) of CBD and CBG for S. mutans and C. albicans and the metabolic activity of a subgingival 33-species biofilm under CBD and CBG treatments were determined. The Quantification of cytokines was performed using the LEGENDplex kit (BioLegend, Ref 740930, San Diego, CA, USA).
Results: CBD-treated cell viability was greater than 95%, and for CBG, it was higher than 88%. MIC for S. mutans with CBD was 20 µM, and 10 µM for CBG. For C. albicans, no inhibitory effect was observed. Multispecies biofilm metabolic activity was reduced by 50.38% with CBD at 125 µg/mL (p = 0.03) and 39.9% with CBG at 62 µg/mL (p = 0.023). CBD exposure at 500 µg/mL reduced the metabolic activity of the formed biofilm by 15.41%, but CBG did not have an effect. CBG at 10 µM caused considerable production of anti-inflammatory mediators such as TGF-β and IL-4 at 12 h. CBD at 10 µM to 20 µM produced the highest amount of IFN-γ.
Conclusion: Both CBG and CBD inhibit S. mutans; they also moderately lower the metabolic activity of multispecies biofilms that form; however, CBD had an effect on biofilms that had already developed. This, together with the production of anti-inflammatory mediators and the maintenance of the viability of mammalian cells from the oral cavity, make these substances promising for clinical use and should be taken into account for future studies.”
“The role of bacteria, together with the production of anti-inflammatory mediators and the maintenance of the viability of mammalian cells from the oral cavity, make these substances promising for clinical use and should be considered for future in vivo studies. In the near future, it will be useful to study Cannabis derivatives uses on biofilm formation as well as to functionalize different regeneration biomaterials with cannabinoids, which could be a useful approach to improve clinical outcomes after periodontal therapy.”
“Objective: The aim of this study was to: (1) evaluate the anti-inflammatory effects of cannabidiol (CBD) on primary cultures of human gingival fibroblasts (HGFs) and (2) to clinically monitor the effect of CBD in subjects with periodontitis.
Background: The use of phytocannabinoids is a new approach in the treatment of widely prevalent periodontal disease.
Materials and methods: Cannabinoid receptors were analyzed by western blot and interleukin production detected using enzyme immunoassay. Activation of the Nrf2 pathway was studied via monitoring the mRNA level of heme oxygenase-1. Antimicrobial effects were determined by standard microdilution and 16S rRNA screening. In the clinical part, a placebo-control double-blind randomized study was conducted (56 days) in three groups (n = 90) using dental gel without CBD (group A) and with 1% (w/w) CBD (group B) and corresponding toothpaste (group A – no CBD, group B – with CBD) for home use to maintain oral health. Group C used dental gel containing 1% chlorhexidine digluconate (active comparator) and toothpaste without CBD.
Results: Human gingival fibroblasts were confirmed to express the cannabinoid receptor CB2. Lipopolysaccharide-induced cells exhibited increased production of pro-inflammatory IL-6 and IL-8, with deceasing levels upon exposure to CBD. CBD also exhibited antimicrobial activities against Porphyromonas gingivalis, with an MIC of 1.5 μg/mL. Activation of the Nrf2 pathway was also demonstrated. In the clinical part, statistically significant improvement was found for the gingival, gingival bleeding, and modified gingival indices between placebo group A and CBD group B after 56 days.
Conclusions: Cannabidiol reduced inflammation and the growth of selected periodontal pathogenic bacteria. The clinical trial demonstrated a statistically significant improvement after CBD application. No adverse effects of CBD were reported by patients or observed upon clinical examination during the study. The results are a promising basis for a more comprehensive investigation of the application of non-psychotropic cannabinoids in dentistry.”
“Odontogenic pain can be debilitating, and nonopioid analgesic options are limited. This randomized placebo-controlled clinical trial aimed to assess the effectiveness and safety of cannabidiol (CBD) as an analgesic for patients with emergency acute dental pain. Sixty-one patients with moderate to severe toothache were randomized into 3 groups: CBD10 (CBD 10 mg/kg), CBD20 (CBD 20 mg/kg), and placebo. We administered a single dose of respective oral solution and monitored the subjects for 3 h. The primary outcome measure was the numerical pain differences using a visual analog scale (VAS) from baseline within and among the groups. Secondary outcome measures included ordinal pain intensity differences, the onset of significant pain relief, maximum pain relief, changes in bite force within and among the groups, psychoactive effects, mood changes, and other adverse events. Both CBD groups resulted in significant VAS pain reduction compared to their baseline and the placebo group, with a maximum median VAS pain reduction of 73% from baseline pain at the 180-min time point (P < 0.05). CBD20 experienced a faster onset of significant pain relief than CBD10 (15 versus 30 min after drug administration), and both groups reached maximum pain relief at 180-min. Number needed to treat was 3.1 for CBD10 and 2.4 for CBD20. Intragroup comparisons showed a significant increase in bite forces in both CBD groups (P < 0.05) but not in the placebo group (P > 0.05). CBD20 resulted in a significant difference in mean percent bite force change in the 90- and 180-min time points compared to the placebo group (P < 0.05). Compared to placebo, sedation, diarrhea, and abdominal pain were significantly associated with the CBD groups (P < 0.05). There were no other significant psychoactive or mood change effects. This randomized trial provides the first clinical evidence that oral CBD can be an effective and safe analgesic for dental pain.”
“This study showed for the first time that pure CBD could provide more than 70% analgesia to patients with emergency dental pain and increase their bite force during the analgesic effect while maintaining a safe drug profile with minimal side effects. This novel study can catalyze the use of CBD as an alternative analgesic to opioids for acute inflammatory pain conditions, which could ultimately help to address the opioid epidemic.”
“Strategies to promote dental pulp stem cells (DPSCs) functions including proliferation, migration, pro-angiogenic effects, and odontogenic/osteogenic differentiation are in urgent need to restore pulpitis-damaged dentin/pulp regeneration and DPSCs-based bone tissue engineering applications. Cannabidiol (CBD), an active component of Cannabis sativa has shown anti-inflammation, chemotactic, anti-microbial, and tissue regenerative potentials. Based on these facts, this study aimed to analyze the effect of CBD on DPSCs proliferation, migration, and osteogenic/odontogenic differentiation in basal and inflammatory conditions. Highly pure DPSCs with characteristics of mesenchymal stem cells (MSCs) were successfully isolated, as indicated by the results of flowcytometry and multi-lineage (osteogenic, adipogenic, and chondrogenic) differentiation potentials. Among the concentration tested (0.1-12.5 µM), CBD (2.5 μM) showed the highest anabolic effect on the proliferation and osteogenic/odontogenic differentiation of DPSCs. Pro-angiogenic growth factor VEGF mRNA expression was robustly higher in CBD-treated DPSCs. CBD also prompted the migration of DPSCs and CBD receptor CB1 and CB2 expression in DPSCs. TNF-α inhibited the viability, migration, and osteogenic/odontogenic differentiation of DPSCs and CBD reversed these effects. CBD alleviated the TNF-α-upregulated expression of pro-inflammatory cytokines TNF-α, interleukin (IL)-1β, and IL-6 in DPSCs. In conclusion, our results indicate the possible application of CBD on DPSCs-based dentin/pulp and bone regeneration.”
“We tested the effect of CBD on DPSCs functions required for dentin and pulp revitalization and bone regeneration, including viability, migration, osteogenic/odontogenic differentiation, pro-angiogenic potential, and anti-inflammatory effects in vitro experiments. Our results showed the anabolic effect of CBD in these functions of DPSCs both in the basal and inflammatory situations suggesting the possible application of CBD or/and DPSCs on oral tissue regeneration including dentin/pulp and bone. Our results warrant in situ studies using dentin/pulp and bone regeneration models to further confirms these anabolic roles of CBD.”
“Background: As effective immune modulators, Endocannabinoids may suppress the inflammatory responses in periodontitis. This study assessed the expression of cannabinoid receptors in gingiva and the impact on periodontitis.
Methods: A cross-sectional study on 20 patients with more than stage II and Grade A periodontitis and a control group consisting of 19 healthy individuals was performed. The gingival biopsies were assessed for the expression of CB1 and CB2 using the quantitative reverse transcription polymerase chain reaction, TaqMan method.
Results: The study sample consisted of 39 subjects, 31 females (79.5%) and 8 males (20.5%), including 20 periodontitis subjects (80% female and 20% male), and control groups (78.9% female and 21.1% male). The mean ages of cases and controls were 33.3 ± 4.7 and 35.7 ± 5.1 years, respectively. The gene expression of CB2 in periodontitis was 27.62 ± 7.96 and in healthy subjects was 78.15 ± 23.07. The CB2 was significantly lower than the control group (p = .008). In comparison, the gene expression index of CB1 in the periodontal group (9.42 ± 3.03) was higher than the control group (6.62 ± 1.13) but did not meet a significant value (p = .671).
Conclusion: The lower expression of CB2 receptors in the periodontitis group may be due to the reduced protective effect of anti-inflammatory agents. These elements include cannabinoids and the imbalance leading to the predominance of pro-inflammatory effects. Therefore, the local effects of cannabinoids as an immunomodulator could be useful for oral inflammatory diseases such as periodontitis.”
“In conclusion, as CB2 receptors are expressed in gingival tissues, particularly immune cells and fibroblasts, they involve in tissue and wound repair. The lower expression of these receptors in periodontitis, could be related to the inflammatory reactions and interrupts wound repair. Therefore, it seems that the use of cannabinoid CB2 agonists in the form of mouth wash contributes to the healing of periodontitis.”
